J-moxoeane



Patented Apr. 28, 1953 1,3-DIOXLANEL'DERIVATIVESAN METHOD 0F PREPARING THE SAME LeortE; Tenenljaum', Brooklyn, andiilohn V..Scudi;,

New York, NJ. 15., assignors to Nenera. Ghemical- Cot Ino., Nenera Park, Yonkers, N. Y., acorpc ratiomoitNew-Yorki bio-Drawing. Application .l'une12, 1951',

Serial-No. 231,258

8 Claims. 1:

invention relates to: new hs-dioxolane compounds, and particularly relates to" 4-(0- methylnlienoxymethyl li, 1 ,3-di'o'Xolanes substitilted in the 2'- pos-itiorr and a method of preparing them.

More specifically, it-relates tosuch compounds in which one 0t the" liyd'rogens in the 2- position may be substituted by a lower alkyl" group and the other hydrogen is'subs-tit'uted by a loweredkoxy group. By the term lower alkyl and lower alkoxy groups we mean radicals with one to five carbon atoms.

The compounds of this series-of dioxolane derivatives are valuable for therapeutic purposes. They are biologically active substances, which exert a depressant action on the central nervous systems they earn be administered safely as: they possessarelativelylow' degre'eof toxicity.

The probable: general formula of these"v come pounds is:-

(3H3 waits-sawdus- Q lin which R represents hydrogen. or a lower alkyl group, and R5 represents, a lower allsoxy group.

Qur. new compounds are prepared, according to the method of our invention, by heating 1-(0- methylphenoxyl-ZB-dihydroxypropane with an excess of a lower alkyla orthoester of a lower alkyl carboxylic acidaccording, to the equation:

We distill off the alcohol formed and at least half of the excess orthoester and then fractionate the residue in vacuum. We may add a catalytic 2 quantity (i. e. front about 1% to about 5%; by weight of the. dihydroxypropane derivative of sulfuric acid or other esterification catalyst to the reaction, but in most cases we have found it to be unnecessary.

The following are several illustrative examples of some of the preferred procedures of carrying out our invention, and of the products obtained thereby, which are given forillustration and not limitation;

Example 1 73" grams of 1-(o inethylphenoxy) zfi dlhy droxypropane and ZOO'gra'ms of methyl ortho nvalerate-were heated in a distilling'flask with l' mini concentrated sulfuric acid until the tern perature of the distillate reached C. at which point no more-methanol came-over. Theheatiinlput was then raised so that the temperature of the distillate reached 165 C; and kept'there until about one-halt ot the excess methyl: ortho n- Valerate came over. The residue was thendistilled under reduced pressure. The product, 2- butyl 2' methoxy 4' (0' methyl'ph'enoxy methyl)'--l,3-dioxolanewas collected atlfifi C. at 5' mm.

Analysis oi th'elproduct" showed: (3":6 9.0%,H:8j4l%. (Calculated' for c n o4 68.6 8.63

Example 2 37 grains of 1-(o-methylphenoxy)-2,3-dihyroxypropane and 106 grams of. ethyl orthopropionate was. gently heated in: adistilling flask vith 1 ml. of concentrated sulfuric acid until the temperature or" the distillate reached C. at which point no more ethanol: came over. The heatinput. was then raised so that the temperature of the distillate reached 163 C. and kept there until: about one halfof the excess ethyl orthopropionate came over; The residue was then distilled under reduced pressure;v The prod uct, 2 ethyl 2'- ethoxy (o methylphenoxyinethyl) -l,3-dioxolane,, was collected at 194'- 1955 C. at. 27 mm Analysis of the product showed: G:6S10"%",-H:8367%1 (Caloulatedf'or- (3 112204 67.6 833 Example 3 37 grams of l-(o methylphenoxy) -2,3-dihydroxypropane and 97 grams of ethyl orthoacetate were heated in a distilling flask until the temperature of the distillate reached 90 C. at which point no more ethanol came over. The heat input was then raised so that the temperature of the distillate reached C. and kept there until about one-half of the excess ethyl orthoacetate 3 came over. The residue was then distilled under reduced pressure. The product. 2-methyl-2- ethoxy 4 (o-methylphenoxymethyl) 1,3 dioxolane, was collected at 171-172" C. at 14 mm.

Analysis of the product showed: C=66.6%, H=8.00% (Calculated for C H O 66.6 7.99)

Example 4 73 grams of l-(o-methylphenoxy)-2,3-dihydroxypropane and 200 grams of methyl orthoacetate were heated in a distilling flask until the temperature of the distillate reached C. at which point no more methanol came over. The heat input was then raised so that the temperature of the distillate reached C. and kept there until about one-half of the excess methyl orthoacetate came over. The residue was distilled under reduced pressure. The product, 2- methyl-2-methoxy-4- (o-methylphenoxymethyl) 1,3-dioxolane, was collected at 144 C. at 8 mm.

Analysis of the product showed: C:6.9%, H:7.52% (Calculated for C13H1s04.

Example 5 37 grams of l-(o-methylphenoxy)-2,3-dihydroxypropane and 148 grams ethyl orthoformate were heated in a distilling flask with 1 ml. of concentrated sulfuric acid until the temperature of the distillate reached 92 C. at which point no more ethanol came over. The heat input was then raised so that the temperature of the distillate reached 150 C. and kept there until about one-half of the excess ethyl orthoformate came over. The residue was then distilled under reduced pressure. The product, 2-ethoxy-4-(omethylphenoxymethyl)-l,3-dioxo1ane, was collected at -176 C. at 15 mm.

Analysis of the product showed: (3:65.492, H=7.58% (Calculated for C1SH1SO4 65.5 7.6.1)

In each example, the analytical results checked the calculated, or theoretical, within normally accepted limits.

The 2-substituted,2 alkoxy,4 (o-methylphenoxymethyl) ,2,3-dioxolanes of our invention are colorless liquids at room temperature. They are insoluble in water and aqueous alkali solutions. They decompose in dilute acids. They are soluble in the common organic solvents such as a1- cohol, ether, acetone, benzene, ligroin and pyridine. They are also soluble in animal and vegetable oils.

Pharmacological studies show that our new compounds exert a depressant action on the central nervous system and are relatively low in toxicity. They may be effectively administered either orally or parenterally, We have administered them orally either in a liquid emulsion or a powder form. For the former, we have dissolved 2 g. of the substituted dioxolane in 40 ml. of propylene glycol and then added water to a total volume of 100 m1. For administration in powder form we have mixed 2 g. of the substance with starch paste and, after drying, diluted the mixture with milk sugar to a total weight of 100 grams. For parenteral injection, 2 g. of the compound was dissolved in almond, cottonseed, or olive oil. Other inert or otherwise physiologically acceptable solids or liquids may also be used as menstrua.

Having so described our invention, we do not limit ourselves to the specifically mentioned times, temperatures, quantity of chemicals or steps of procedure as these are given simply to clearly describe our invention as set forth in our specification and claims, and they may be varied without going beyond the scope of our invention.

We claim:

1. The process for producing 2-alkyl,2-alkoxy, 4 (o-methylphenoxymethyl) 1,3 dioxolanes, comprising the steps of reacting l-(o-methylphenoxy)-2,3-dihydroxypropane with an orthoester. distilling ofi the by-product alcohol formed and the unreacted excess of the orthoester and col lecting the product so formed by distillation under reduced pressure.

2. The process for producing 2alkyl,2-alkoxy, 4 (o-methylphenoxymethyl) 1,3 dioxolanes, comprising the steps of reacting l-(o-methylphenoxy)-2,3-dihydroxypropane with an orthoester in the presence of catalytic amounts of an esterification catalyst, distilling ofi the by-product alcohol formed and the unreacted excess of the orthoester and collecting the product so formed by distillation under reduced pressure.

3. 2-alkyl,2 alkoxy,4-(o-methylphenoxymeth yl) -1,3-dioxolanes of the general formula:

in which R is selected from the members of a group consisting of hydrogen and lower alkyl radicals with one to five carbon atoms and R represents a lower 'alkoxy radical having one to five carbon atoms.

4. 2 butyl,2 methoxy,4 (o-methylphenoxymethyl) ,1,3-dioxolane.

5. 2-ethyl,2 ethoxy,4-(o-methylphenoxymethyl) ,1,3-dioxolane.

6. 2 methyl,2 ethoxy,4 (o-methylphenoxymethyl) ,1,3-dioxolane.

7. 2-methyl,2 methoxy,4-(o-methylphenoxymethyl) ,1,3diox01ane.

8. z-ethoxy l-(o-methylphenoxymethyl) ,1,3-dioxolane.

LEON E. TENENBAUM. JOHN V. SCUDI.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,028,403 Mares Jan. 21, 1936 2,286,791 Dickey June 16, 1942 OTHER REFERENCES Virtue Proceedings Society Experimental Biology and Medicine, February 1950, pp. 259 to 262.

Yoder, J. A. Chemical Society, vol. 45 (1923), pp. 475 to 479. 

3. 2-ALKYL,2- ALKOXY,4-(O-METHYLPHENOXYMETHYL)-1,3-DIOXOLANES OF THE GENERAL FORMULA: 